Abstract Transgender women?especially racial minority transgender women?have HIV prevalence that is far higher than any other population segment in the United States. Nearly two-thirds of transgender women meet CDC criteria for pre-exposure prophylaxis (PrEP) indication but only 5% report ever taking PrEP. Most prior HIV prevention research has lumped together transgender women in a single category with men who have sex with men (MSM) even though these sexual and gender minority (SGM) groups may face different life challenges and have very different needs. Except for a handful of small focus group studies conducted in large cities on the East and West coasts, very little research has systematically explored factors responsible for low PrEP use among transgender women at high risk for contacting HIV infection and identified ways to increase PrEP adoption and sustained use. This proposal?submitted in response to Notice OD-20-032?requests an SGM administrative supplement to add a sample of racial minority transgender women to parent grant R01- NR017574, a project that tests approaches to increase PrEP use among African American MSM in Milwaukee and Cleveland, both Midwestern cities with stark HIV disparities. The supplement will employ a mixed-methods research design with 60 high-risk racial minority transgender women recruited from the community who will be added to the parent grant. During study visits, each woman will participate in a semi-structured in-depth interview to elicit perceptions, understandings, and beliefs about PrEP; concerns and barriers to PrEP use; factors that would facilitate the adoption and sustained use of PrEP; and preferences about PrEP delivery modalities and service access. Interviews will delve into how PrEP can be presented to transgender women in ways that affirm a positive, healthful, and proud sense of gender identity that counteracts the deleterious influence of intersectional stigma. In-depth interviews will be recorded, transcribed, coded, and qualitatively analyzed to identify how best to optimize and tailor interventions to reach and benefit the HIV prevention and health needs of transgender women. Participants will also be administered measures that are being employed in the parent grant to assess HIV testing and health history, sexual practices, substance use, and PrEP use knowledge, attitudes, behavioral intentions, norm perceptions, and self-efficacy, as well as a measure of gender minority stress and resilience validated with transgender and gender nonconforming persons. These quantitative data will be analyzed to identify whether?and how?the HIV prevention needs of racial minority transgender women differ from those of racial minority MSM as well as factors that facilitate or impede PrEP use among transgender women. Findings of this research will improve the field?s understanding of HIV health needs of transgender minority women?a vulnerable, understudied, and underserved SGM community population?and will inform implementation efforts to achieve the goals of the National Plan to End the HIV epidemic.